Pancreatic cancer is the fourth leading cause of cancer related deaths in the US. Although surgical resection is the only curative option, the median survival is only 15-19 months for resectable stage 1,2 and 3 disease. For patients who present with metastatic disease, the median survival is 3-6 months. The addition of chemotherapy and/or radiation therapy in select settings have resulted in only modest clinical benefits. Therefore, more effective therapies are urgently needed. The central theme of this grant proposal is to optimize immunotherapy for pancreatic cancer by designing and conducting clinical trials using genetically modified pancreatic tumor cell lines as vaccine that would improve on the outcome of: (1) patients with pancreatic adenocarcinoma following surgical resection when given in combination with chemoradiation (Specific Aim #1); and (2) patients with primary metastatic or relapsed disease when given in sequence with immune modulating doses of Paclitaxel or with cytoreductive doses of Gemcitabine (Specific Aim #2). [unreadable] [unreadable] We hypothesize that: (1) Biologic endpoints that include the measurement of post vaccination delayed type hypersensitivity (DTH) responses to autologous tumor (adjuvant study) or to mutated k-ras peptides (metastatic study) and the measurement of the immune infiltration at the vaccine site can correlate with clinical endpoints such as overall and disease-free survival. (2) Measurement of serum GM-CSF levels as a measure of longevity of the vaccine cells following each vaccination can provide an improved understanding of the in vivo kinetics of the allogeneic cells at the vaccine site and will allow for the optimization of the vaccine boosting schedule. (3) The vaccine is associated with minimal toxicities and can be safely integrated with chemotherapy and radiation therapy. The design of Specific Aim #1 is a single institution Phase II study of vaccine in combination with adjuvant chemoradiotherapy for the treatment of pancreatic adenocarcinoma following surgical resection. The study will enroll 60 patients over 2 years. The design of Specific Aim #2 is a single institution randomized study of vaccine in sequence with Gemcitabine or with Paclitaxel in patients with primary metastatic or relapsed pancreatic adenocarcinoma. This study will enroll 120 patients over 2 years. [unreadable] [unreadable] If these studies demonstrate anti-tumor immunity that is associated with prolongation of disease free survival, they will lead to the design and conduction of multi-center phase III studies. Ultimately, these studies could lead to the approval of a new therapeutic option for pancreatic cancer, which is currently fatal in most patients. In addition, data from these studies could contribute to a better understanding of how to schedule multiple vaccine boosts. Finally, these data will provide valuable information on how to best integrate the vaccine with other therapeutic modalities including surgery, radiotherapy and chemotherapy. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]